The microbicidal activity exerted by several peroxidases in the presence of hydrogen peroxide and a halide ion has been well established. Such systems also possess potent cytotoxic activity when instead of hydrogen peroxide a H2O2-generating system is used. Thus the NADPH oxidase/myeloperoxidase/chloride syustem may be responsible for the killing of prokaryotes during phagocytosis. It has been amply demonstrated that such cytotoxic systems are active against a variety of eukaryotes as well, and little specificity for any one target cell has thus far been demonstrated. Using the glucose oxidase/horseradish peroxidase/chloride system we have demonstrated that this system readily kills certain tumor cells in vivo with a high degree of specificity. Thus 20-25 gram Novikoff hepatomas in rats underwent complete remission in about 10 days upon the administration of this cytotoxic system with no apparent damage to any normal tissue. Remissions were also observed with a lymphosarcoma, a melanoma,and a breast adenocacinoma. The cytotoxic system needs to be immobilized onto an insoluble support in order to obtain these results. During this grant period we wish to investigate 1) the mechanism by which the cytotoxic enzyme system distinguishes a tumor cell from a normal cell; 2) the events occurring in the membrane of the target cell that eventually lead to lysis; and 3) do a comparative study with various peroxidases to evaluate their effectiveness as antitumor agents. Our long-term objective is to attempt to elucidate the exact role of peroxidases in the following processes: 1) the initiation of specific immune responses; 2) the natural defense of the body against cell transformatin; 3) normal cell turnover in vivo; and 4) the cause of certain degenerative diseases.